Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• the present invention relates to a method for preparing an intermediate of sitagliptin which is an antidiabetic drug.
• Sitagliptin is a triazolopiperazine compound having a beta-amino acid structure and has the chemical name of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3- ⁇ ]pyrazin-7(8H)-yl) -1-(2,4,5-trifluorophenyl)butan-2-amine.
• Sitagliptin was developed by US company, Merck & Co., Inc.
• Sitagliptin is the first DPP-IV inhibitor to treat type 2 diabetes and is currently commercially available in countries around the world as an antidiabetic drug under the brand name Januvia in the form of a sitagliptin phosphate monohydrate.
• sitagliptin “t-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3- ⁇ ]pyrazin-7(8H)-yl)-1-(2,4, 5-trifluorophenyl)-4-oxobutan-2-ylcarbamate” (Compound 2 in Reaction Scheme 1 below) is prepared as in Reaction Scheme 1 and is disclosed in U.S. Pat. No. 6,699,871.
• Reaction Scheme 1 disadvantageously employs expensive reaction reagents, 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and exhibits a very low product yield. Therefore, this method is not suitable for industrial-scale application.
• HOBT 1-hydroxybenzotriazole
• EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
• the present invention is intended to provide a method for preparing a compound of formula 2 which is economical due to the use of inexpensive reagents and exhibits an excellent product yield and is therefore suitable for industrial-scale mass production.
• the present invention provides a method for preparing a compound of formula 2. which includes reacting a compound of formula 3 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- ⁇ ]pyrazine or a salt thereof in an organic solvent in the presence of 2-chloro-4,6-dimethoxy-1,3,5-triazine and a tertiary organic amine.
• R is t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), acetyl or benzoyl.
• the compound of formula 3 used as a starting material is commercially available or may be prepared by the method of INTERMEDIATE 3 disclosed in U.S. Pat. No. 6,699,871, Column 23.
• the compound of formula 3 of the present invention when R is Cbz, Fmoc, acetyl or benzoyl, the corresponding compound may be prepared by using benzyl chloroformate, fluorenylmethyloxycarbonyl chloride, acetyl chloride or benzoyl chloride in place of di-tert-butyldicarbonate in Step B of the production method of INTERMEDIATE 3 disclosed in U.S. Pat. No. 6,699,871, Column 23.
• 2-chloro-4,6-dimethoxy-1,3,5-triazine which corresponds to a compound of formula 4 below, may be commercially available.
• 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- ⁇ ]pyrazine which corresponds to a compound of formula 5 below used as a reactant in the present invention, or a salt thereof is commercially available or may be prepared by the method disclosed in U.S. Pat. No. 6,699,871.
• the salt of the compound of formula 5 may be in the form of a hydrochloride, sulfate, phosphate, methanesulfonate or p-toluenesulfonate thereof.
• tertiary organic amine refers to a base which is commonly used for the formation of an amide bond in the field of organic chemistry.
• examples of the tertiary organic amine include N-methylmorpholine, pyridine, triethylamine, trimethylamine, triisopropylamine and quinoline.
• reaction molar ratio of the compound of formula 3:the compound of formula 5 in the present invention may vary but is preferably in the range of 1:0.8 to 3 and more preferably 1:1.1 to 1.3.
• reaction molar ratio of the compound of formula 3:the compound of formula 4 in the present invention may vary but is preferably in the range of 1:1 to 3 and more preferably 1:1.1 to 1.4.
• reaction molar ratio of the compound of formula 3:N-methylmorpholine in the present invention may vary but is preferably in the range of 1:2 to 5, more preferably 1:2.5 to 4.0 and most preferably 1:3.
• the organic solvent used in the present invention may be a common organic solvent which is used for an amide-forming reaction in the field of organic chemistry.
• the organic solvent is preferably selected from the group consisting of tetrahydrofuran, N,N-dimethylformamide, toluene and dichloromethane.
• the preparation method of the present invention may be carried out at a wide range of temperatures which do not cause side reactions, but is carried out at a reaction temperature of about 0 to about 35° C. and preferably about 0 to 30° C. Specifically, starting materials, reactants and the like are mixed at a temperature of more preferably about 0 to about 10° C. and even more preferably about 0 to about 5° C., followed by warming to room temperature and reaction.
• room temperature refers to a temperature of about 15 to 30° C.
• the preparation method of the present invention may further include crystallizing the compound of formula 2 using at least one solvent selected from ethyl acetate, isopropyl alcohol, ethanol, methanol, dichloromethane, hexane, acetonitrile and tetrahydrofuran.
• at least one solvent selected from ethyl acetate, isopropyl alcohol, ethanol, methanol, dichloromethane, hexane, acetonitrile and tetrahydrofuran.
• Crystallization may be carried out according to a method conventionally used by a person of ordinary skill in the art.
• the present invention provides a method for preparing a sitagliptin phosphate monohydrate, which includes the method for preparing a compound of formula 2 in accordance with the present invention.
• the preparation method of the present invention enables the economical and high-yield production of a compound of formula 2 which is a key intermediate of sitagliptin and is therefore applicable to industrial-scale mass production.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Diabetes (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Obesity (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Endocrinology (AREA)
• Hematology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Emergency Medicine (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

Applications Claiming Priority (3)

Publications (2)

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Cited By (4)

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Citations (12)

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• 2011
  • 2011-01-20 KR KR1020110006081A patent/KR101290029B1/ko not_active Expired - Fee Related
• 2012
  • 2012-01-18 US US13/977,919 patent/US9006436B2/en not_active Expired - Fee Related
  • 2012-01-18 WO PCT/KR2012/000408 patent/WO2012099381A2/en not_active Ceased
  • 2012-01-18 JP JP2013550394A patent/JP5735659B2/ja not_active Expired - Fee Related
  • 2012-01-18 PT PT127371714T patent/PT2665728E/pt unknown
  • 2012-01-18 CN CN201280006060.3A patent/CN103403008B/zh not_active Expired - Fee Related
  • 2012-01-18 EP EP12737171.4A patent/EP2665728B1/de not_active Not-in-force
  • 2012-01-18 ES ES12737171.4T patent/ES2550342T3/es active Active

Patent Citations (14)

Non-Patent Citations (23)

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